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J Phys Chem B. 2010 Dec 16;114(49):16263-72. doi: 10.1021/jp108056s. Epub 2010 Oct 11.

Conformational dynamics in human purine nucleoside phosphorylase with reactants and transition-state analogues.

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Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, United States.


Dynamic motions of human purine nucleoside phosphorylase (hPNP) in complex with transition-state analogues and reactants were studied using 10 ns explicit solvent molecular dynamics simulations. hPNP is a homotrimer that catalyzes the phosphorolysis of purine 6-oxynucleosides. The ternary complex of hPNP includes the binding of a ligand and phosphate to the active site. Molecular dynamics simulations were performed on the ternary complex of six ligands including the picomolar transition-state analogues, Immucillin-H (K(d) = 56 pM), DADMe-Immucillin-H (K(d) = 8.5 pM), DATMe-Immucillin-H (K(d) = 8.6 pM), SerMe-Immucillin-H (K(d) = 5.2 pM), the substrate inosine, and a complex containing only phosphate. Protein-inhibitor complexes of the late transition-state inhibitors, DADMe-Imm-H and DATMe-Imm-H, are inflexible. Despite the structural similarity of SerMe-Imm-H and DATMe-Imm-H, the protein complex of SerMe-Imm-H is flexible, and the inhibitor is highly mobile within the active sites. All inhibitors exhibit an increased number of nonbonding interactions in the active site relative to the substrate inosine. Water density within the catalytic site is lower for DADMe-ImmH, DATMe-Imm-H, and SerMe-Imm-H than that for the substrate inosine. Tight binding of the picomolar inhibitors results from increased interactions within the active site and a reduction in the number of water molecules organized within the catalytic site relative to the substrate inosine.

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